scholarly journals Leptin Secreted in the Testicular Microenvironment Promotes the Endogenous Function of Leydig Cells Through Hedgehog Signaling Pathway

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A769-A769
Author(s):  
Himanshu Arora ◽  
Madhumita Parmar ◽  
Kajal Khodamoradi ◽  
Rehana Qureshi ◽  
Joshua M Hare ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Leydig Cells ◽  
Hedgehog Signaling ◽  
Stem Cell Differentiation ◽  
Health Concern ◽  
Myoid Cells ◽  
Paracrine Factors ◽  
Testosterone Production ◽  
Adult Leydig Cells

Abstract Objective: Testosterone deficiency (TD) is a common health concern, affecting around 1 in 5 men globally. However, the factors responsible for TD remain largely unknown. Leydig cells produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. Leydig stem cells (LSC) have the potential to differentiate into adult Leydig cells, which can increase testosterone levels; however, the factors promoting differentiation are unknown. In the present study we evaluated the paracrine factors released from the testicular microenvironment (TME) (comprised of Sertoli and peritubular myoid cells) that modulate the differentiation of Leydig stem cells to adult Leydig cells. Additionally, we explored the underlying mechanism of action of these paracrine factors. Methods: Tissue samples were obtained from a total of 13 men with testicular failure, who underwent testis biopsies for sperm retrieval. Using an IRB approved protocol, about 10mg of testicular tissue from each sample were processed for LSC isolation, culturing, and characterization. Cytokine antibody array was performed to identify the paracrine factors released by Sertoli and peritubular myoid cells using unsorted and CD146+ve sorted cells. The cells were treated with hedgehog signaling agonist and antagonist to validate the specificity of paracrine factors identified. Immunostaining was performed to evaluate changes at the protein level. Flow cytometry was performed to study the shift in the population of cells post leptin treatment. GraphPad Prism (GraphPad Software) was used for statistical analysis. Results: This study revealed that the TME plays an instrumental role in Leydig stem cell differentiation and testosterone production through regulation of the desert hedgehog (DHH) signaling pathway. TME-secreted leptin induces LSC differentiation and increases testosterone production. However, these effects are inversely concentration-dependent: positive at low leptin doses and negative at higher leptin doses. Mechanistically, leptin acts on LSCs upstream of DHH in a unidirectional fashion, as DHH gain or loss of function was shown to have no effects on Leptin levels. Conclusions: These findings identify leptin as a key paracrine factor released by cells within the TME that modulate LSC differentiation and testosterone production from adult Leydig cells, a finding that is key to developing new niche therapies for TD.

scholarly journals Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes

2016 ◽  
Vol 113 (10) ◽  
pp. 2666-2671 ◽  
Author(s):  
Xiaoheng Li ◽  
Zhao Wang ◽  
Zhenming Jiang ◽  
Jingjing Guo ◽  
Yuxi Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Lineage ◽  
Seminiferous Tubules ◽  
Paracrine Factors ◽  
Adult Testis ◽  
Adult Leydig Cells ◽  
Neonatal Testis

Testicular Leydig cells are the primary source of testosterone in males. Adult Leydig cells have been shown to arise from stem cells present in the neonatal testis. Once established, adult Leydig cells turn over only slowly during adult life, but when these cells are eliminated experimentally from the adult testis, new Leydig cells rapidly reappear. As in the neonatal testis, stem cells in the adult testis are presumed to be the source of the new Leydig cells. As yet, the mechanisms involved in regulating the proliferation and differentiation of these stem cells remain unknown. We developed a unique in vitro system of cultured seminiferous tubules to assess the ability of factors from the seminiferous tubules to regulate the proliferation of the tubule-associated stem cells, and their subsequent entry into the Leydig cell lineage. The proliferation of the stem Leydig cells was stimulated by paracrine factors including Desert hedgehog (DHH), basic fibroblast growth factor (FGF2), platelet-derived growth factor (PDGF), and activin. Suppression of proliferation occurred with transforming growth factor β (TGF-β). The differentiation of the stem cells was regulated positively by DHH, lithium- induced signaling, and activin, and negatively by TGF-β, PDGFBB, and FGF2. DHH functioned as a commitment factor, inducing the transition of stem cells to the progenitor stage and thus into the Leydig cell lineage. Additionally, CD90 (Thy1) was found to be a unique stem cell surface marker that was used to obtain purified stem cells by flow cytometry.

scholarly journals Targeting the Hedgehog Signaling Pathway by Glasdegib Limits the Self- Renewal of MDS-Derived Induced Potent Stem Cells (iPSC)

2017 ◽  
Vol 09 (06) ◽  
Author(s):  
Tetsuzo Tauchi ◽  
Seiichi Okabe ◽  
Seiichiro Katagiri ◽  
Yuko Tanaka ◽  
Kaoru Tohyama ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
The Self ◽  
Hedgehog Signaling Pathway ◽  
Self Renewal

scholarly journals Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Shiqin Li ◽  
Meng Wang ◽  
Yanghui Chen ◽  
Wei Wang ◽  
Junying Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Adult Stem Cells ◽  
Reproductive Function ◽  
Future Research ◽  
Germline Stem Cells ◽  
Proliferation And Differentiation ◽  
Hh Signaling

Germline stem cells (GSCs) are adult stem cells that are responsible for the production of gametes and include spermatogonial stem cells (SSCs) and ovarian germline stem cells (OGSCs). GSCs are located in a specialized microenvironment in the gonads called the niche. Many recent studies have demonstrated that multiple signals in the niche jointly regulate the proliferation and differentiation of GSCs, which is of significance for reproductive function. Previous studies have demonstrated that the hedgehog (Hh) signaling pathway participates in the proliferation and differentiation of various stem cells, including GSCs in Drosophila and male mammals. Furthermore, the discovery of mammalian OGSCs challenged the traditional opinion that the number of primary follicles is fixed in postnatal mammals, which is of significance for the reproductive ability of female mammals and the treatment of diseases related to germ cells. Meanwhile, it still remains to be determined whether the Hh signaling pathway participates in the regulation of the behavior of OGSCs. Herein, we review the current research on the role of the Hh signaling pathway in mediating the behavior of GSCs. In addition, some suggestions for future research are proposed.

scholarly journals Exosomes of Antler Mesenchymal Stem Cells Improve Postoperative Cognitive Dysfunction in Cardiopulmonary Bypass Rats through Inhibiting the TLR2/TLR4 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Chun Yang ◽  
Shengnan Sun ◽  
Qi Zhang ◽  
Jia Guo ◽  
Tengfei Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiopulmonary Bypass ◽  
Signaling Pathway ◽  
Cognitive Dysfunction ◽  
Postoperative Cognitive Dysfunction ◽  
Paracrine Factors ◽  
Tlr4 Signaling ◽  
Tlr4 Agonist ◽  
Tlr4 Signaling Pathway

Postoperative cognitive dysfunction (POCD) is a severe complication of cardiopulmonary bypass (CPB) and has common characteristics such as acute cognitive dysfunction, impaired memory, and inattention. Mesenchymal stem cells (MSCs) are multipotent cells that have therapeutic potentials mainly through paracrine action via secreting growth factors and cytokines. Exosomes are one of the important paracrine factors and have been reported as potential cell-free therapy for the treatment of autoimmune and central nervous system disorders. In this study, we examined exosomes derived from antler MSCs (AMSCs) of POCD rats after CPB and evaluated their potential regulatory mechanisms. AMSC-derived exosomes reduced neurological damage and brain damage and prevent apoptosis in CPB rats. Furthermore, AMSC-derived exosomes were found to reduce hippocampal neuronal apoptosis and the expression of TLR2, TLR4, MyD88, and NF-κB in CPB rats. However, the above effects of AMSC-derived exosomes on CPB rats were abolished partially by toll-like receptor 2/4 (TLR2/TLR4) agonist (LPS-EB). In conclusion, AMSC-derived exosomes can improve cognitive function in CPB rats through inhibiting the TLR2/TLR4 signaling pathway.

In Vitro Osteoinductive Effects of Hydroxycholesterol on Human Adipose-Derived Stem Cells Are Mediated through the Hedgehog Signaling Pathway

2014 ◽  
Vol 134 (5) ◽  
pp. 960-968 ◽  
Author(s):  
Anisa Yalom ◽  
Akishige Hokugo ◽  
Sarah Sorice ◽  
Andrew Li ◽  
Luis A. Segovia Aguilar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
Adipose Derived Stem Cells

scholarly journals LncRNA-Hh Strengthen Cancer Stem Cells Generation in Twist-Positive Breast Cancer via Activation of Hedgehog Signaling Pathway

Stem Cells ◽  
2015 ◽  
Vol 34 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Mingli Zhou ◽  
Yixuan Hou ◽  
Guanglun Yang ◽  
Hailong Zhang ◽  
Gang Tu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
Positive Breast Cancer

scholarly journals Exosomes Derived From Human Adipose-Derived Stem Cells Inhibit Lipogenesis Involving Hedgehog Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Ziwan Ji ◽  
Zhongming Cai ◽  
Shuming Gu ◽  
Yucang He ◽  
Zikai Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Expression Profiles ◽  
Adipogenic Differentiation ◽  
Clinical Applications ◽  
Adipose Derived Stem Cells ◽  
High Fat ◽  
Hh Signaling

Since obesity impairs wound closure and adipose-derived exosomes (ADEs) regulate wound healing in clinical applications, we hypothesized that ADEs may inhibit adipogenesis of adipose-derived stem cells (ADSCs) to reduce the adverse effects of obesity on wound healing. Hedgehog (Hh) signaling has been previously shown to inhibit adipogenesis in ADSCs. The present study aimed to determine the role of ADEs in the adipogenesis of ADSCs and the Hh signaling pathway. ADSCs collected from human adipose tissues were co-cultured with ADEs and treated with an adipogenic inducer. qRT-PCR showed that ADEs could inhibit adipogenic differentiation of ADSCs and activate Hh signaling. The differences in the mRNA expression profiles of genes related to Hh signaling between the groups that were exposed to either high fat or low fat indicated that increased Hh signaling activation is necessary but not sufficient to inhibit adipogenic differentiation in the ADSC differentiation process. The Hh signaling pathway can be activated effectively by ADEs, especially during high-fat exposure after treatment with ADEs. Oil Red O staining of adipocytes suggested that ADEs inhibited not only adipogenic differentiation, but also lipogenesis in ADSCs. Overall, targeted activation of Hh signaling by ADEs reduced lipid accumulation in ADSCs and may be explored for clinical applications.

scholarly journals Expression of Wnt5a defines the major progenitors of fetal and adult Leydig cells

2020 ◽  
Author(s):  
Herta Ademi ◽  
Isabelle Stévant ◽  
Chris M Rands ◽  
Béatrice Conne ◽  
Serge Nef
Keyword(s):  
Leydig Cells ◽  
Clonal Expansion ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Myoid Cells ◽  
Adult Testis ◽  
Large Numbers ◽  
Bona Fide ◽  
Adult Leydig Cells

SummaryLeydig cells (LCs) are the major androgen-producing cells in the testes. They arise from steroidogenic progenitors, whose origins, maintenance and differentiation dynamics remain largely unknown. Here, we identified Wnt5a as a specific marker of steroidogenic progenitors, whose expression begins at around E11.5-E12.5 in interstitial cells of the fetal mouse testis. In vivo lineage tracing indicates that Wnt5a-expressing progenitors are initially present in large numbers in the fetal testis and then progressively decrease as development progresses. We provide evidence that Wnt5a-expressing cells are bona fide progenitors of peritubular myoid cells as well as fetal and adult LCs, contributing to most of the LCs present in the fetal and adult testis. Additionally, we show in the adult testis that Wnt5a expression is restricted to a subset of LCs exhibiting a slow but noticeable clonal expansion, revealing hitherto unappreciated proliferation of fully differentiated LCs as a contribution to the adult LC pool.

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